Fertilization, Implantation & Early Pregnancy Loss
From sperm activation to implantation, and where it goes wrong
Fertilization
Meiotic timing. Primary oocytes enter meiosis in fetal life and arrest in prophase I for years. The LH surge completes meiosis I just before ovulation, producing a secondary oocyte and the first polar body; the ovulated secondary oocyte then arrests in metaphase II and completes meiosis II only if a sperm enters, releasing the second polar body. Fertilization usually occurs in the ampulla of the fallopian tube within about a day of ovulation.
- CapacitationOver several hours in the uterus and tube, cholesterol and seminal glycoproteins are stripped from the membrane over the acrosome; Ca2+ influx rises and motility becomes hyperactivated. Sperm leaving the epididymis are motile but cannot yet fertilize.
- Corona penetrationSperm hyaluronidase disperses the corona radiata.
- Acrosome reactionBinding to zona pellucida glycoproteins (classically ZP3) triggers release of acrosin and other enzymes that digest a path through the zona.
- Membrane fusionSperm and oocyte membranes fuse, and a Ca2+ wave sweeps the oocyte.
- Cortical (zona) reactionCortical granules exocytose enzymes that modify zona glycoproteins, so the zona hardens and rejects further sperm.
- ZygoteMeiosis II completes; male and female pronuclei combine.
If the block to polyspermy fails, two sperm can fertilize one egg (dispermy), producing triploidy such as a 69,XXY partial hydatidiform mole.
Early development and implantation
First week. The zygote cleaves as it moves down the tube, reaching the uterus as a morula around day 3–4. Fluid accumulates to form a blastocyst: the inner cell mass becomes the embryo and the outer trophoblast becomes the placenta. The blastocyst hatches from the zona around day 5 and begins implanting about day 6 after fertilization, usually into the posterior wall of the uterine body, whose endometrium is in the secretory phase.
Trophoblast and hCG. The trophoblast forms an inner cytotrophoblast (the mitotic stem layer) and an outer syncytiotrophoblast (multinucleated and invasive). The syncytiotrophoblast secretes human chorionic gonadotropin (hCG), detectable in maternal blood about 8 days after fertilization and in urine around the time of the missed period. hCG acts on LH receptors to rescue the corpus luteum, which keeps secreting progesterone until the placenta takes over late in the first trimester. Levels roughly double every 48 hours early in a normal pregnancy and peak at about 8–10 weeks. hCG shares its α subunit with LH, FSH and TSH; its β subunit gives specificity and is what pregnancy tests detect.
Ectopic pregnancy
Site and risk. More than 95% of ectopic pregnancies are tubal, most often in the ampulla. Anything that slows transport of the embryo raises risk: a prior ectopic (the strongest factor), pelvic inflammatory disease from Chlamydia or gonorrhea, tubal surgery or ligation, endometriosis, IVF and smoking. An IUD lowers the overall chance of pregnancy, but a pregnancy that occurs with an IUD in place is disproportionately ectopic.
Pathology. Pregnancy hormones decidualize the endometrium wherever the embryo implants. Uterine curettage in a tubal pregnancy therefore shows decidua without chorionic villi, often with the Arias-Stella reaction (hypersecretory glands with enlarged, hyperchromatic nuclei). Arias-Stella change is a hormone effect also seen in intrauterine pregnancy; the telling finding is the absence of villi. The tube itself contains villi and hemorrhage.
Presentation. Symptoms typically begin 6–8 weeks after the last period with amenorrhea, pelvic pain and spotting. Trophoblast erodes the thin tubal wall until it ruptures, causing hemoperitoneum, hypotension, peritoneal signs and shoulder-tip pain from diaphragmatic irritation. Transvaginal ultrasound shows no intrauterine sac despite a positive β-hCG and may show an adnexal mass and free fluid in the rectouterine pouch. Stable, unruptured cases can be treated with methotrexate, a folate antagonist that kills dividing trophoblast; rupture requires surgery.
Pregnancy loss and hyperemesis
Spontaneous abortion. Loss before 20 weeks ends about 10–15% of clinically recognized pregnancies, mostly in the first trimester. About half of first-trimester losses are chromosomally abnormal: autosomal trisomies form the largest group (trisomy 16 is the most common), followed by 45,X and triploidy. Aneuploidy, and thus miscarriage risk, rises with maternal age.
| Cause | Mechanism | Clue or action |
|---|---|---|
| Antiphospholipid syndrome | Lupus anticoagulant, anticardiolipin or anti-β2-glycoprotein I antibodies → placental thrombosis | Prolonged aPTT that does not correct with mixing; heparin plus low-dose aspirin (warfarin is teratogenic) |
| Uterine anomaly | Septate uterus; poorly vascularized septum | Hysteroscopic evaluation and resection |
| Parental balanced translocation | Unbalanced gametes → aneuploid embryos | Karyotype both partners |
| Endocrine disease | Poorly controlled diabetes or thyroid disease | Optimize control before conception |
Hyperemesis gravidarum. Persistent first-trimester vomiting with more than 5% weight loss, ketonuria and dehydration; loss of gastric acid produces a hypokalemic, hypochloremic metabolic alkalosis. It clusters with high-hCG states such as molar pregnancy and multiple gestation, and hCG's weak TSH-like action can cause transient gestational hyperthyroidism (low TSH, mildly raised free T4).
Give thiamine before dextrose in prolonged vomiting to avoid precipitating Wernicke encephalopathy.